This background section synthesizes the most relevant publications and knowledge in the field as seen by one of the inventors (RJM) after successful completion of the invention. Many of the observations and statements are made with the benefit of hindsight. Thus, none of the statements made in the background section is to be construed as representative of the knowledge of those ordinarily skilled in the art as of the filing date.
There are a number of biological characteristics of HIV and its interaction with host defense mechanisms that have so far frustrated the development of effective therapies, including both protective and therapeutic vaccines. Infection with HIV results in multiorgan, intracellular infection that has both a cytolytic and latent stage. There has been a limited number of effective antiretroviral drugs developed to date and these have been associated with the eventual and sometimes rapid development of drug resistance with subsequent clinical deterioration. While there is need to pursue new primary drug therapy of HIV, immune-based therapy, both passive and active, has been recognized as a potential approach to the HIV-infected individual.
It has been felt that an effective HIV vaccine or immunotherapeutic will need to induce a specific and protective cytotoxic T lymphocyte (CTL) response as well as a neutralizing antibody response. Recent studies on the rapid turnover of plasma HIV virions as well as CD4 lymphocytes in HIV-infected individuals have demonstrated that while a low CD4 count corresponds to disease progression, even at markedly depressed CD4 counts, the immune system maintains the ability to mount an effective immune response. Therefore, the HIV-infected individual with advanced AIDS could still have an immune system capable of recognizing and responding to antigenic structures in an appropriately formulated therapeutic vaccine.
Although there is a strong humoral and cellular immune response to primary infection by HIV, in general, this response does not result in long term protection from clinical disease progression, including Acquired Immunodeficiency Syndrome (AIDS). For example, the antigenic variation in the HIV envelope protein has made the development of effective glycoprotein vaccines problematic. Vaccine induced antibody may not be protective against homologous or heterologous strains of HIV. Thus, the success of active therapeutic and prophylactic vaccines or immunotherapies may depend on the ability of the host immune system to recognize and respond to HIV-related and associated antigens in new ways.
One strategy to the preparation of therapeutic vaccines and immunotherapies has been to remove antigenic material (plasma, blood cells, or tissue) from a given patient and process (formulate) the material ex vivo with an adjuvant or immunomodulating agent. These reformulated, patient-specific antigen preparations are then administered to the patient. The goal is to attempt to increase or redirect the immune response to specific antigenic regions, or even to entice the immune system to respond to potentially protective but "hidden", (sequestered) antigens. In addition, the types or balance of the immune responses induced could be altered in a way that results in better clinical outcomes. Such changes would include but are not limited to: humoral versus cell mediated responses, classes of antibody subtypes, T helper cell subsets, activation of T cytotoxic and natural killer cells, and secretion of soluble molecules involved in regulating immune responses, including cytokines and chemokines. This type of formulation has been termed an autogenous vaccine.
The use of autogenous vaccines (AV) has been limited to a few bacteria and several viral-tumor models. For example, the possibility that the immune system is capable of mounting an effective immune response against tumors under certain conditions has been suspected for almost 100 years. This notion is based primarily on the rare but documented phenomenon of spontaneous regression of tumors. However, this notion is also supported by data from in vitro systems that have identified a wide variety of tumor-specific antigens as well as by the development of animal models in which immunization against such antigens resulted in rejection of the tumor cells. In addition, there have been many attempts to utilize immune modulators as therapy for tumors but these have resulted in only a small number of successes. Since human tumors tend to be poorly immunogenic, continued efforts have been made to find substances that can enhance the immune response to tumors.
For more than 60 years, it has been known that on occasion tumors regressed following naturally occurring viral infections. This phenomenon has been called "viral oncolysis." Enveloped viruses including influenza virus, vaccinia virus, and Newcastle disease virus have all been used to induce human tumor regression. Recently, it has been shown, using a model tumor antigen system, that immunizations with recombinant vaccinia virus or recombinant fowlpox virus can stimulate a CTL response sufficient to produce reductions in tumor burden in vivo.
One of the inventors (JMO) has successfully demonstrated the use of AV therapy for the treatment of the papilloma virus induced disease of recurrent juvenile laryngeal papillomata. Over the last 24 years, twenty-eight children with severe recurrent juvenile papilloma of the larynx have been treated with AV's. In these patients, none has had a worsening of tumor growth while 20 (71%) have had a marked reduction or clearing of their tumors.